4,5-DIMETHOXY-2-ETHOXYAMPHETAMINE

#76 EMM

4,5-DIMETHOXY-2-ETHOXYAMPHETAMINE

SYNTHESIS: A solution of 166 g 3,4-dimethoxybenzaldehyde in 600 mL
acetic acid was well stirred, and brought up to an internal
temperature of exactly 25 °C. There was added, in very small
portions, a 40% solution of peracetic acid in acetic acid. The
evolved heat was removed with an external ice bath, and the rate of
addition was dictated by the requirement that the internal temperature
should not exceed 25 °C. A total of 210 g of the 40% peracetic acid
was used. The reaction mixture was poured into 3 L H2O, and the
acetic acid neutralized by the addition of solid K2CO3. The neutral
aqueousphase was extracted with 5x150 mL Et2O, and the solvent from
the pooled extracts was removed under vacuum. To the red-colored
residue there was added 300 mL 10% NaOH, and the mixture was heated
for 1 h on the steam bath. This was cooled, washed once with CH2Cl2,
acidified with HCl, and extracted with 5x150 mL Et2O. The pooled
extracts were washed once with saturated NaHCO3 (which removed most of
the color) and the removal of the solvent under vacuum gave 105 g of
3,4-dimethoxyphenol as an amber oil that slowly set up to crystals.

The above crude 3,4-dimethoxyphenol was dissolved in 200 mL EtOH, and
treated with a solution of 38.1 g KOH in 300 mL hot EtOH. The clear
solution of the potassium salt was a deep red color, and was promptly
treated with 94.3 g allyl bromide, at a rate commensurate with the
exothermic reaction. The mixture was held at reflux for 2 h. This
was then added to 1 L H2O and extracted with 5x100 mL Et2O. The
extracts were pooled, and removal of the solvent under vacuum gave a
residue of 98 g of a black oil. This was distilled at 104-108 °C at
0.7-1.0 mm/Hg to give 59.3 g 1-allyloxy-3,4-dimethoxybenzene as a pale
yellow oil with a greenish cast.

A total of 59 g of the neat 1-allyloxy-3,4-dimethoxybenzene was
provided with an internal thermometer, and heated with an open flame.
The color quickly became purple, then lightened to a red at 70 °C, and
finally to a pale pink by 210 °C. At 240 °C an exothermic reaction
set in with the temperature going up to almost 290 °C. It was held in
the 270-280 °C range for several min, then allowed to return to room
temperature. GC analysis showed two peaks, the second and major one
being the desired 1,2,4,5-isomer. A small sample was caught by
prep-GC, and it successfully seeded the crude Claissen rearrangement
product. The isolated 2-allyl-4,5-dimethoxyphenol, pressed on a
porous plate, had a mp of 39.5-40.5 °C which was improved to 41.5-42
°C by recrystallization from hexane.

EXTENSIONS AND COMMENTARY: This was the first of the ethoxy homologues
of TMA-2, and it was immediately (well, within a couple of months) run
up from an initial dab to 25 milligrams. This was in early 1963, and
the lack of activity of EMM was keenly disappointing. This was a
level at which the prototype, TMA-2, was very active, and the
conclusion was that maybe any change on the molecule would result in a
loss of activity. So this approach was shelved for a while, and all
efforts were directed into the relocation, rather than the elongation,
of the methoxy groups. A few months later, the ethoxy question was
addressed again, and the discovery of MEM rekindled full interest in
this ethoxy question.